In recent years, extensive efforts have been focused on developing compounds that can simultaneously act as muscarinic antagonists and β₂-adrenoceptor agonists, holding great promise as bronchorelaxant treatments for patients with asthma or COPD. Such heterobifunctional compounds offer several advantages, including their potential to address formulation challenges and enhance efficacy through allosteric interactions.
The preferred delivery platform for such therapies is through inhalation, which demands the application of an "inhalation by design" approach, since achieving the right balance of physicochemical properties for optimal target engagement in the lungs is of paramount importance. We introduced an additional layer of complexity to our design by adopting a "super soft-drug" strategy to maximize the therapeutic window of the molecules by minimizing systemic effects.
Our medicinal chemistry efforts led us to CHF-6366, a clinical candidate demonstrating well-balanced in vivo efficacy at individual receptors, with effects lasting up to 24 hours post-dosing. Administered via inhalation, it maintains the desired persistence and stability in the lungs.
CHF-6366 undergoes extensive liver and plasma hydrolytic metabolism, leading to two primary metabolites with reduced efficacy, resulting in an excellent in vitro and in vivo safety profile. Consequently, it advanced to clinical studies as a nebulized solution.
In a pursuit of a suitable backup compound, we aimed to differentiate our new MABAs from CHF-6366. This involved developing plasma-stable compounds with high plasma protein binding and hepatic clearance to reduce systemic exposure. Our approach also emphasized the importance of attaining a crystalline form as a mandatory requirement before advancing in development. Following extensive exploration, CHF-6550 emerged as the most promising candidate exhibiting the desired "soft-drug" behaviour, the required sustained in vivo efficacy and an ideal solid-state profile suitable for dry powder inhaler (DPI) development.

Nicola Cesari

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